This paper illustrates “monarch, minister, assistant and envoy”
principle of traditional Chinese medicine through clinical treatment
guideline of rheumatoid arthritis. The conception can promote the
precise treatment in rheumatoid arthritis management, and prevent
side effects of drugs consciously. To applicant the “monarch, minister,
assistant and envoy” principle to direct clinical drug options for
rheumatoid arthritis may facilitate a more flexible, safer, and less drug
intake.

Rheumatoid arthritis is a long-lasting autoimmune disease
in clinic, which typically results in warm, swollen and painful
joints, the waist and hands are most commonly involved. The
progression of the disease can cause irreversible deformity. It
can also affect other parts of the organs or systems, and result in
anemia, fatigue, inflammation around the lungs, atherosclerosis,
and inflammation around the heart [1-3]. Besides of function loss
of extremities, diverse complications especially infection is risk
factors for early death in these patients [4]. The prevalence of
rheumatoid arthritis is around 0.5%-1% in advanced countries,
some 49,000 people died of rheumatoid arthritis in 2010
worldwide [5,6]. Due to the high incidence and disability and
mortality rates, along with the huge medical research investment,
variety of drugs has been exploited providing sundry options
for clinical management. Excessive treatment, side effects from
drugs and overrating benefits from pharmacies are issues needs
alertness.

Obviously, it is not personalized enough to solve complains
of each patient through frigidly execution of authoritative
guidelines or recommendations published. Is there a way or
principle of selecting drugs for more accurate treatment for
rheumatoid arthritis patients? Traditional Chinese Medicine
(TCM) gained afflatus from war that similar principles dominate
in both military and medicine that is to prescribe drugs according
to military action strategies or country governance [7,8]. For
example, it is recorded in Yellow Emperor (Huangdi Neijing)
that army force should be prepared to eliminate invasion, it
would be too late to establish military force when an invasion
is breaking out. Medication is prescribed to cure diseases; and
medicine should not be given delayed until illness progressed.
Military strategies and medicine share a same truth. Another
quotation from Military Base (Bin lei) says, an eminent general
conducts troops resembles an eminent doctor applies of
drugs. It needs to change drugs proactively if an illness state
changed instantaneously. However, if an illness fluctuated while
prescription revising not followed, none of the diseases could
be cured. It is summarized the roles of drugs in a prescription
formula as Jun (Monarch), Chen (Minister), Zuo (Assistant) and
Shi (Envoy) in TCM theories, which we think could be enlighten
our modern medical recipes for rheumatoid arthritis patients as
well.

Conceptions of Jun, Chen, Zuo and Shi

Jun, Chen, Zuo and Shi originally means Monarch, Minister,
Assistant and Envoy four types of people in a government, and
currently is used to expound various herbs of different functions
in a TCM prescription formula. The theory was first recorded in
Shennong Bencao Jing (Variorum of Shennong’s Classic of Materia
Medica), and was recorded and discussed by following medical
literatures of successive dynasties in Chinese history, such as
Yellow Emperor, Treatise on Spleen and Stomach and Medicine
Origin etc.. Jun, Chen, Zuo and Shi is one of the most basic theories
in TCM for prescribe herbal medical formula.

In a formula, the monarch drugs called Jun, which refer
to the drugs that target the disease or main symptoms suffered;
it reflects the main direction the prescription treating. Jun is
an indispensable drug in a formula. Chen drugs are used to
assistant Jun to enhance the effectiveness for the main disease
or symptoms. Zuo means assisting drugs, which may show roles
in three aspects. Firstly, they used to treat subordinated diseases.
Secondly, they help to relive or eliminate toxicities or side effects
caused by Jun and Chen drugs. Thirdly, they were used to exhibit
opposite effects of Jun drugs nevertheless are necessary for
certain situation for a patient. Shi is translated to envoy, refers to
drugs guiding other drugs in a formula to achieve organs involved,
Jingluo attacked or disease location. Shi also helps to harmonize
drugs in a formula to eliminate pathogens.

In this Chinese classical literature, it describes 108 plucky
men organize themselves to revolt the enslaving from corrupt
government. Each person with its talent and has a corresponding
role in the team to fight, which shares a same truth in a
prescription of multiple drugs with different but should have a
well organized function for disease. (Figure 1)

Figure 1: A poster of Water Margin

Medications for RA classified according to Jun,
Chen, Zuo, Shi

Emergence in the 1970s, the term Disease Modifying Anti-
Rheumatic Drugs (DMARDs) is a category of otherwise unrelated
drugs defined by their use in rheumatoid arthritis to slow
down disease progression of joints erosion, to relieve synovial
inflammation, and to improve body function [9]. According
to 2015 American College of Rheumatology (ACR) guideline
for the treatment of rheumatoid arthritis [10], no matter early
diagnosed or established RA, from low diseases to moderate and
high disease activity, DMARD monotherapy is regarded as the
first line option. In circumstance that patients with inflammation
relapse or treatment failure with DMARD monotherapy, options
of combination of DMARDs or DMARDs added to glucocorticoids
or TNFi are recommended. In a word, DMARDs are irreplaceable
medication and the main effective drugs for RA management. So
DMARDs are regarded as Jun drugs. If single DMARD or combined
DMARDs cannot control the symptoms, or the disease still
relapses, low dosage of glucocorticoids is recommended. If the
disease activity is still in middle to high degree, biological agents
would be considered for these intractable cases. Glucocorticoids
and biological agents are used to strengthen the effectiveness on
the basis of DMARDs, so they are assimilated to Chen drugs.

Methotrexate is the first option of DMARDs. The
mechanisms of methotrexate in treatment of rheumatoid arthritis
including inhibiting neutrophil chemotaxis [13], down regulating
pro-inflammatory cytokines such as TNF-α, IFN, IL-6 et al [14].
Methotrexate has many side effects; the most commonly seen
is inhibiting synthesis of folic acid. So taking folic acid or folinic
acid next day after intake of methotrexate is recommended, by
which to prevent gastrointestinal side effects, liver damage,
anemia and leucopenia [15,16]. Obviously, folic acid is a Zuo drug
for methotrexate to relive or eliminate toxicities or side effects
caused. Similarly, side effects caused by all types of DMARDs or
glucocorticoids, should be avoided through withdrawal the drug,
or combining with medication to anti side effects. As most drugs
may have side effects for gastrointestinal tract, and peptic ulcer
is 2 times of general in rheumatoid arthritis population [17]. So a
gastric mucosal protective agent is recommended to rheumatoid
arthritis patients for regular taking.

The conception of Shi (envoy drug) is far-fetched if
introduced to rheumatoid arthritis treatment, so it is not
discussed in this article.

Benefits of utilizing Jun, Chen, Zuo, Shi principle

Administer drugs flexibly

TCM has a profound acquaintance in the development of a
disease with yin-yang and Yi (changing) theories, which contain
a full-order system of changing. Treatment based on syndrome
differentiation was run through the full course of diagnosis
and treatment, progression and prognosis. The conception has
distinguished advantages than today’s medicine. During active
phase of rheumatoid arthritis with joints pain, application of
glucocorticoids, which binding to both monomeric and dimeric
glucocorticoid receptor or injecting which into particular
cavity directly would result in anti-inflammatory effects so as
to relieve symptoms of pain and swollen rapidly [18]. That is
to say we regard glucocorticoids as Jun drugs during active
phase of rheumatoid arthritis. Rheumatoid arthritis can involve
respiratory system, cardiovascular system, nerve system, liver,
kidney and eye and causes various complications [5]. In a certain
disease period or a specific patient, a complication may have
more threatening risk for life, and became the major symptom
for the patient. The drugs target the fatal complication regarded
as Jun drugs, while DMARDs have a Chen status. These instances
indicate the utilization of Jun, Chen, Zuo, Shi could pave a flexible
way of selecting drugs. And ultimately, the personalized accurate
treatment option could be achieved.

Administer drugs safely

Supplement of folic acid as Zuo during MTX is
taken; supplement of vitamin D and calcium as Zuo during
glucocorticoids is taken. Recheck of blood counts, liver and
kidney function regularly while taking DMARDs, TNFi or other
immunosuppressive agents, to prevent infection. Timely aware,
and stop or replace the drugs if side effects appeared. So if we bear
the conception of Jun, Chen, Zuo, Shi in mind, a safer medication
application could be achieved.

Prescribe less medications

As rheumatoid arthritis is a systemic chronic disorder,
clinical individual patients may have various complications.
And under current medical system, more specifically, there is an
interdependent relation between doctors and pharmaceutical
manufacturers, patients exposed to the risk of excessive medical
treatment vulnerably. However, the increased risk of side effects
is accompanied by each drug added. Sometimes, the so called
Evidence Based Medicine is an authoritative tool of smiling hurt
prescribed from doctors’ HIS (hospital information system). Few
clinicians or pharmacists can fully illustrate the metabolic process
and interference between drugs clearly if a patient taking more
than 5 drugs. During clinical practice, we find that to prescribe
medications under Jun, Chen, Zuo, Shi theory will not increase
the medications chosen, on the contrary, it is a conception for
prescribing more concisely in rheumatoid arthritis and other
diseases as well.

Conclusions and prospects

Rheumatoid arthritis is characterized by synovial
inflammation and hyperplasia (“swelling”), autoantibody
production (rheumatoid factor and Anti–Citrullinated Protein
Antibody [ACPA]), cartilage and bone destruction (“deformity”),
as well as systemic features, including cardiovascular, pulmonary,
psychological, and skeletal disorders [4]. The abundant basic
researches in rheumatoid arthritis have accelerated new drugs
for the disease, which has resulted in a marked improvement in
clinical outcomes. The current treatment strategy can reflect this
achievement, once been diagnosed, and the disease activity is
accessed, positive treatment would be followed. Through there
is no treatment cures rheumatoid arthritis; the therapeutic goals
are a remission of symptoms involving the joints, a return of full
function, and the maintenance of remission. Unfortunately, there
is still a part of patients received partial or failed of remission,
sustained remission is rarely achieved and most patients requires
ongoing pharmacologic therapy, and mortality rate is higher
among patients than healthy persons, and systemic complications
remain a major challenge. Therefore, rheumatologists need to
be carefully and fully understand the holistic condition of each
individual patient, apply of Evidence Based Medicine and clinical
guidelines rationally. Traditional Chinese medicine, which has
been inherited for thousands of years, apply of state governance
and military tactics to medical treatment figuratively, and produce
a Jun, Chen, Zuo, Shi combination principle of prescription.
We do not think it is outdated if applied to modern medicine.
In this paper, we assimilate DMARDs to Jun, glucocorticoids
and biological agents were assimilated to Chen, while drugs
confronting side effects caused by Jun and Chen including folic
acid, drugs for protecting liver and stomach, calcium and vitamin
D supplements were assimilated to Zuo. Under such instruction,
drugs could be selected concisely and safely. Doctors need
observe patients’ disease activity, complications continuously,
and arrange the status of drugs according to severity and priority
for each patient. For example, in an acute phase, glucocorticoids
may play the role of Jun to relieve joints pain in a short time. Or
for a rheumatoid arthritis patient with acute onset of coronary
heart disease, antithrombotic agents may play the role of Jun.
Under this principle, doctor can administer drugs flexibly and
personalized, deepen the preventive consciousness for side
effects, so as to prescribe rationally and avoid of overtreatment.

Rheumatoid arthritis is still regarded as hazardous
diseases through there are many drugs for choosing, published
guidelines for following. This article discussed the Jun, Chen, Zuo,
Shi principle for guidelines of modern medicines with insufficient
instances. However, there is no corresponding part of Shi (envoy)
drugs in modern drugs, and to category drugs according to Jun,
Chen, Zuo, Shi based on efficacy, utility, toxicity need to be further
investigated.